Thursday, November 6, 2008

New Zoloft study: an eerie case of deja vu

Between teaching journalism and working on my master's thesis, I have only now found the time to scrutinize the much-heralded Zoloft study published last Friday in the online version of The New England Journal of Medicine. And I have a few bones to pick with it, some of which have already been picked by commentators on Pharmalot.

The study found that a combined regimen of Zoloft and cognitive behavior therapy was more effective than either the drug or therapy alone in treating anxiety in children (age 7 to 17). It also concluded that Zoloft and CBT by themselves were more effective than placebo. News accounts of the study trumpeted the fact that none of the children in this trial committed suicide and that there was no significant increase in suicidal thoughts among those taking Zoloft. By highlighting these findings, the study's researchers no doubt intended to add weight to the argument that the FDA acted too hastily back in 2004 in putting black box warnings on Zoloft and other antidepressants.

Not so fast please. If you look closely at the data in this study, there are indications that a number of children taking Zoloft did have adverse reactions to the drug and experienced "a worsening" of psychiatric behaviors, in one case so severe that the child required hospitalization. Indeed of the three children in thte study who had serious adverse effects, two of them were in the Zoloft only arm of the study and one in the combination arm. Yet the study researchers dismiss the case requiring psychiatric hospitalization as being "unrelated to the study treatment."

This language of blithe dismissal is eerily reminscient of another antidepressant trial: Paxil study 329, which is currently under investigation by the U.S. Department of Justice back story. In study 329, researchers not only dismissed some adverse effects as being unrelated to Paxil, but they also concluded that Paxil was more effective than placebo, when in fact the data showed it was not. (As I reveal in my book, Side Effects, Brown University researchers also misrepresented data in the trial, coding teenagers who were suicidal as being "noncompliant."

Indeed, as Doug Bremner, professor of psychiatry at Emory University, points out on Pharmalot, the results of this study are not that different from the non-statistically significant results in the Paxil study. In that study, Paxil was found to be no more effective than placebo on the two primary outcome measures. In the more recent Zoloft study, Bremner notes that when you look at the actual data on one of the primary outcomes, the Pediatric Anxiety scale, the difference in improvement between the patients in the Zoloft only arm and the patients in the placebo group are also not statistically significant. Bremner dissects problems with the Zoloft study in greater depth on his blog.

There's more. The Zoloft study also minimizes the fact that of the 14 patients who withdrew from either treatment or the study due to adverse side effects, most of them were in the Zoloft only group. While its authors make much of the finding that there were no patients with suicidal thoughts in the Zoloft only group, they gloss over the fact that there were five patients who expressed suicidal ideation in the combined Zoloft/CBT group.

The researchers also ignore the finding that overall, there were many fewer side effects among the children in the cognitive behavior therapy group alone; patients in the latter group reported fewer cases of insomnia, fatigue, sedation, restlessness and fidgeting than those in the Zoloft study. That makes a lot of sense given the research showing that there is an increased risk of akathasia (agitation and restlessness) among patients who take SSRI antidepressants like Zoloft, Prozac and Paxil.

Finally, the Zoloft trial shares another disturbing similarity with Paxil study 329: in the fine print at the end of the NEJM report, its researchers disclose a myriad of financial ties to the pharmaceutical industry, including extensive consulting and speaking fees from companies that make SSRI antidepressants. So as several of the Pharmalot commentators ask, why should we trust the conclusions of this study? Why indeed.

8 comments:

Marilyn said...

Doug Bremner also discussed the study on his blog:

http://www.beforeyoutakethatpill.com/2008/10/sertraline-kids.html

Marilyn Mann

Amy said...

As a participant in this study with my then 11 year old daughter...I think our experience needs to be heard.
The stress on my daughter and our family of her experiencing severe anxiety and panic attacks since she was 2 was something I would never wish on anyone.
When I made the phone call to inquire about the study I was sceptic that anything out there would help her.
My daughter ended up with the zoloft and behavior modification.The process was very time consuming and emotionaally draining to say the least. But we dealt with the most caring, understanding people imaginable at UPMC in Pittsburgh.
I had a child that could feel the turmoil in her body before the study. As the study progressed, the changes were a miracle.
I needed to express this because we are real families that felt hopeless about what we were dealing with. I don't know where we would be today if we had not had success with this study.
I felt a need to comment so people can understand that there are real families behind the numbers. And for right now...We have more than hope that she will become whatever she wants to...and not be held back by the crippling effects of Anxiety.

Thank You, Amy from Pittsburgh

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toolateforsome said...

I took zoloft after finding out my mother had cancer and would be staying with me for her treatment I was already in therapy for a anxiety after an accident and my doctor said it was a psychological upper.
My experience I wanted to drive my car into a wall and kill us both now if that is worth the manic like energy you get to make to all the cancer treatment appointments maybe this drug is for you. If you beat the suicidal homicidal tendancies....
Dark humour aside there is something really wrong with this drug don't take it.
Most of these type of drugs have been found to be no more effective than sugar pills, have severe side effects and withdrawal plus you may kill yourself or one you love as they often make sane people CRAZY. Don't take the chance it is not woth it you can get the same energy from more coffee.
To check on the side effects/ effectiveness and withdrawal from antidepressants or if you are currently in withdrawal from a ssri or snri and need help check this site.
paxilprogress.org

Discover What You Think said...

Serotonin Enhancing Psychotropic Pharmaceuticals

In the 1930s, physicians approached the mental illness of depression a bit differently that we do today. While acknowledging a likely cause of depression in one of their patients is often due to some great misfortune, they seemed to focus on what is called a complex. A complex is disturbances of ideas and impulses that are the cause of consistent habitual patterns of thought, feelings, and behavior. An example of this state of mind of one who is depressed is one who experiences an exaggerated or obsessive concern or fear. And the etiology for this mental disorder was often undefined. People react differently to life stressors in their life, so depression cannot be empirically determined.
In the 1930s, psychotherapy such as cognitive therapy was recommended for treating the depressed patient, and not pharmacological therapy. Also considered for the depressed patient was positive lifestyle changes that would lessen the pain that the depression was causing them. Try and be grateful, they would tell their patient, as well as thankful and appreciative for whatever good may be in their life, and normally the depressed patient would eventually recover
Times have changed since then.
Presently, serotonin-enhancing drugs are the therapeutic regimens for those who are suspect of having a depressed state, or perhaps the patient simply asks for these types of drugs due to their perception that they are depressed. Furthermore, and remarkably, various other mood disorders one may have can be treated with these drugs, typically called SSRIs. What is remarkable is that the mood disorders which will be discussed later are subject to debate and have also been brought to the attention to so many others through disease awareness campaigns by the makers of these SSRI drugs. So mental flaws claimed to be relieved by SSRI drugs may not be the case at all.
With depression, the most severe cognitive and behavioral malfunctions are expressed in what is called a major depressive disorder, which is also called clinical depression or major depression. Symptoms of this type of depression, which is the most concerning to health care providers in particular due to its severity, include decreased or flat affect, decreased interest in activities once enjoyable, self perceptions of worthiness, guilt, regret, helplessness, and hopeless by the sufferer, to name a few of the diagnostic features that may be present with one who has such a major depressive disorder. The disease has a vexing insistence on staying with the victim for a lengthy period of time- often continuing to progress symptomatically in severity and discomfort. This disease is very disabling, and cannot be lifted by one’s will, so all health care professionals likely agree that depression is a potentially serious condition with their patients. Suicidal ideation and attempts are associated with major depression.
These SSRI drugs mentioned earlier are known by some health care providers as third generation anti-depressants. Such drugs, drugs that affect the mind, are called psychotropic medications. SSRIs also include a few drugs in this class that include the addition of a norepinephrine uptake inhibitor added to the SSRI in one capsule, and these drugs are referred to as SNRI medications. The combination of two different drugs has made them the top class of prescriptions for psychological misalignment.
There are several available SSRIs presently, yet it is believed that only two SNRIs are available, which are Cymbalta and Effexor. Some consider these classes of meds, the serotonin enhancers in these medications, have been considered the next generation mood enhancers- after the benzodiazepine hype decades ago, which was followed by what were called trycyclic drugs for depression for some time. Furthermore, regarding SNRIs, adding the additional agent of norepinepherine is presumed to increase the effectiveness of SSRIs by some, yet not everyone claims relief from these types of drugs.
Some Definitions:
Serotonin is a neurotransmitter thought to be associated with mood. The hypothesis was first suggested in the mid 1960s that this neurotransmitter may play a role in moods and emotions in humans. Yet to this day, the serotonin correlation with such behavioral and mental conditions is only theoretical. In fact, the psychiatrist’s bible, which is known as the DSM, states that the definite etiology of depression remains a mystery and remains unknown with complete certainty. So a chemical imbalance in the brain is not proven to be the cause of mood disorders, it is only suspected as a result of limited scientific evidence. In fact, diagnosing mental diseases such as depression is based on subjective assessment only, as interpreted by the prescriber, so one could question the accuracy of such diagnoses.
Norepinepherine is a stress hormone, which many believe help those who have such mood disorders as depression. Basically, with the theory that by adding this hormone, the SSRI will be more efficacious for a patient prescribed such a med, as suggested earlier.
And the depressive state of a patient certainly can be aggravated by another mood disorder at the same time with some patients. Anxiety usually exists with one who has a major depressive disorder. An objective diagnosis of such a mental condition is rather impossible to assess objectively. Therefore any diagnosis made for a mental abnormality lacks complete accuracy and assurance. Such illnesses can only be assessed conceptually, so the diagnosis or impression concluded by the patient’s health care provider is dependent on subjective criteria expressed by the suspected patient that is not mentally sound. At times, there have been screening programs that have been used for identifying depressed patients have proven to be largely ineffective. A social patient history is uncertain and tricky as well, some have said, yet is obtained often from such patients. There is no objective diagnostic testing for any mental malfunction to validate as to whether or not such a disease is present. A health care provider has to assess as to whether certain non-verbal or vocalized features are present with a patient in order to conclude confidently that one may have in fact some degree or level of depression. To assess a suspected depressed patient is further complicated by the fact that the exact cause of major depression is unknown. Research says that there is a strong genetic component to this illness.
The diagnosis of depression as well as mood disorders that may exist within patients has increased quite a bit over the past few decades. Some have asked themselves, as well as others- actually how many people are really and actually depressed? What is believed is that if one determined to be cognitively impaired from a mental paradigm, then this may be in fact major depression. If this mental disorder is determined by a health care provider, it is possible that pharmacological therapy may be considered reasonable and necessary, as well as psychotherapy either suggested to be performed with or in place of medicinal therapy. Studies show that both therapies working together may be of most benefit for the depressive patient, yet it is not a guaranteed protocol for treatment in this way.
It has been reported that around 10 percent of the U.S. population will at some point be affected by an episode of what may be a major depressive disorder. This is much greater in number than just a few decades ago. Perhaps media sources are to blame, by suggesting to their viewers that they may in fact be depressed. So the diagnosis and medicinal treatment have remarkably increased in a relatively short period of time in the United States. Of course, the expansion of those claimed and determined to be depressed does not sadden the makers of these drugs used to treat this mental disorder one bit, I’m sure.
Some have said that so many more people seek treatment now for what they believe is a major depressive disorder they are experiencing, when in fact it may be possibly intense sadness, perhaps, due to a loss of some sort in their lives. There is a difference, and health care providers should have the appropriate tools and knowledge to discriminate between the two states of mental conditions. Sadness is not a medical problem. Symptoms associated with an unfavorable mental state need to be excessive and chronic to be considered to have in fact the medical problem of a major depressive disorder, as stated by others.
In Time magazine’s June 16th 2008 cover story, it was reported that the military personnel in the Iraq war are pounding down SSRIs often. Every time there is a new war, there is a new drug, it seems. Yet the story may illustrate the frequent usage of these types of medications in a variety of different areas for different reasons. Some reasons may be valid and appropriate, yet others perhaps may not be reasonable for such medicinal therapy. However, as illustrated in this situation, they appear to be accepted as a treatment option without reservation.
In regards to those pharmaceutical companies who make and market such psychotropic drugs in the manner that their manufacturers do is largely unknown to others, such as with screenings performed essentially by front groups, and so forth. However, what is known is that the psychiatry specialty, as they often treats and manages depressed patients, is the one specialty that receives the most monetary funding that is paid to them by these certain pharmaceutical companies for ultimately what they hope will be continued and additional support of the psychotropic meds that they currently promote to these doctors. Needless to say, the desire and the aspect of the pharmaceutical industry clearly is primarily concerned with encouraging as much use out of their products as possible- with both doctors and patients being the route of that increased use they desperately hope will occur.
Regardless, SSRIs and SRNIs are the preferred treatment methods if depression or other mood disorders that are suspected and determined by the health care providers who treat such patients. Yet these drugs discussed clearly are not the only treatments, medicinally or otherwise, for depression and other related and suspected mental disease states, moods, or disorders. Patients should be aware of this fact as well as caregivers. And they may not be aware of the options available to them.
For example, tens of millions of prescriptions are written by health care providers for these types of medications for their patients. These drugs are not inexpensive, either, as it is not unusual for a patient to pay greater than one hundred dollars to have their prescription filled for only a month’s worth of these particular drugs.
Presently, there are about ten different SSRI/SRNI meds available, many of which are now generic, yet essentially, they appear to be similar in regards to their efficacy and adverse events. The newest one, a SNRI called Pristiq, was approved in 2008, and is believed to be launched as a treatment for menopause.
The first one of these SSRI meds was Prozac, which was available in 1988, and the drug was greatly praised for its ability to transform the lives of those who consumed this medication in the years that followed. Some termed Prozac, ‘the happy pill’. In addition, as the years went by and more drugs in this class became available, Prozac was the one of preference for many doctors for children. A favorable book was published specifically regarding this medication soon after it became so popular with others.
Furthermore, these meds have received upon request of their makers to the FDA to have additional indications besides depression for these types of drugs they produce and market, and the indications they have received are for some really questionable conditions , such as social phobia and premenstrual syndrome. Also included with indications that now exist with these types of medications are the quite devastating conditions of what may be mild anxiety and shyness, yet the makers of these drugs consider such patients as having chronic anxiety with severe anxiety disorder, which others have said is rather obsurd. And it gets worse with the indications received for these types of drugs, which now include Obsessive-Compulsive Disorder, Panic Disorder, Agoraphobia, Post Traumatic Stress Disorder, Bulimia, and any form of stress disorders in general. I understand they are seeking indications for pain management as well with these SSRI or SRNI pharmaceuticals. Likely, they will get the indication for their drugs to treat such creative cognitive states apparently others have in great numbers.
With some of these indications for these classes of drugs, I question as to whether or not they are actual and treatable disease states or medical problems. Yet with additional indications for particular drugs in these classes of medications, one can be assured that the market for these drugs will continue to grow- as more are prescribed to those patients who are progressively asking for them specifically for relief they anticipate they will receive from taking these drugs. What such patients are not aware of is that studies have shown that this class of medications is only effective in roughly half of those who take them. And some of the indications granted to drugs in these classes of medications may be considered disease mongering tacitly performed by the makers and marketers of these drugs to again grow the market share for particular drugs of this type. This is combined with drug companies who make these types of meds either forming or creating front groups in order to have more diagnosed with various medical problems that may not exist so their medication can be utilized more. And as mentioned earlier, such pharmaceutical companies have been known to either create or support front groups to ultimately encourage who may be normal people to get evaluated for the diseases indicated with these medications. Of course, such tactics implemented by such pharmaceutical companies are deceptive, inappropriate, unreasonable, unnecessary, and potentially if not actually dangerous to others.
Perhaps of greater concern and danger with these particular psychotropic medications involve the adverse effects associated with these types of drugs, which include suicidal thoughts and actions, violence- including acts of homicide, and aggression- and this is only to name a few. Such events are devastating and have been demonstrated by those who have or are taking these types of drugs. It has been reported that the makers of such drugs are suspected to have known about these toxic and dangerous effects of their drugs and did not share them with the public in a timely and critical manner until forced to do so. While most SSRIs and SNRIs are approved for use in adults only, prescribing these meds to children and adolescents has drawn the most attention and debate with others for understandable reasons, which have included those in the medical profession as well as citizen watchdog groups. The reasons for this attention are due to the potential off-label use of these meds in this population of children, yet what may be most shocking is the fact that some of the makers of these meds did not release clinical study information about the risks of suicide as well as the other adverse events related to such populations, combined with the true decreased efficacy of SSRIs in general, which is believed to be only less than 10 percent more effective than a placebo. Paxil caught the attention of the government regarding this issue of data suppression some time ago, this hiding of such important information- Elliot Spitzer specifically was the catalyst for this awareness, as I recall. Furthermore, that drug is in the spotlight once again years later. Some believe the drug maker knew about possible risk to the youth as early as 1991. Yet did not disclose such danger associated with their drug to the public or the FDA, and this was done with intent.
And there are very serious questions about the use of SSRIs in children and adolescents regarding the possible damaging effects of these meds on them as they get older- these children and teenagers who are prescribed these drugs. Others are asking if this is really necessary- and are these drugs doing more harm than good for their children.
For example, do the SSRIs correct or create brain states considered not within normal limits, which in effect would possibly cause harm rather than benefit a patient on such a drug? Are adolescents really depressed, or just experiencing what was once considered normal teenage angst? Do SSRIs have an effect on the brain development and their self identity of such young people? Do adolescents in particular become dangerous or bizarre due to SSRIs interfering with the myelination occurring within their still developing brains? No one seems to know the correct answer to such questions, yet the danger associated with the use of SSRIs does in fact exist, as demonstrated by others. It is observed in some who take such drugs, but not all who take these drugs. Yet health care providers possibly should be much more aware of these possibilities, possibly, along with the black box warning now on SSRI prescribing information for the youth that has existed since 1994. There are other medications health care providers could prescribe for such patients that have no less benefit for them then the serotonin drugs discussed.
Finally, if SSRIs or SNRIs are discontinued by a patient rapidly, abruptly, and without medical supervision, withdrawals experienced by many of these patients are believed to be quite brutal that follow soon after this drug is not taken anymore by a former patient. This in itself may be a catalyst for one to consider or attempt suicide, others have suggested. Many are aware and understand that discontinuing these SSRIs and SSNIs leaves the brain in a state of neurochemical instability for some great length of time as the neurons need to recalibrate after existing in a brain over-saturated with serotonin and neuron alteration. This occurs to some degree with any psychotropic medication, yet the withdrawals can reach a state of danger for the victim in some classes of meds such as SSRIs and SNRIs, it is believed. And this seems to concern many, yet does not inhibit health care providers for continuing to select such therapy with these drugs for their patients.
SSRIs and SRNIs have been claimed by doctors as well as patients to be extremely beneficial for the patient’s well -being regarding their apparent mental issues that resolve in time. Yet overall, the factors associated with this class of medications may outweigh any perceived benefit for the patient taking such a drug that can harm themselves and others.
Before these medications mentioned were developed, doctors praised trycyclics, another class of anti-depressants mentioned earlier, in a similar manner some time ago. Considering the lack of efficacy that has been demonstrated objectively with these new serotonin specific psychotropics, along with the deadly adverse events with these SSRI and SSNI meds only recently brought to the attention of others, other pharmacological and non- pharmacological treatment options should probably be considered, but that is up to the discretion of the prescriber. And the perception of the benefits derived by these types of drugs may be flawed, as there has been no decrease in incidences of suicide or remission of depression since these drugs have been available, many have concluded. Furthermore, recent studies have suggested that the supplement, St. John’s Wart, has shown to be as effective as medicine for major depression. Deficiencies in vitamins B12 and Folate have been suggested as a cause for depression as well. One study showed that a small jog performed by a depressed patient offered similar if not greater relief than a SSRI drug.
It is my hope that such a prescriber rules out possible other etiologies for their patients’ mental conditions before they conclude that such a patient is suffering from true mental illness requiring the medications mentioned earlier, such as asking their patients about life stressors and other medications these patients have taken or are presently taking. Because at times, a doctor can in fact do harm without intent.
“I use to care, but now I take a pill for that.” --- Author unknown*
Dan Abshear

*Addendum to this article based on the following link recently discovered:

http://www.medicalnewstoday.com/articles/132005.php

There are greater than 60 symptoms associated with one who is or may be depressed, and there are different degrees of depression. The number of symptoms expressed by one who suffers from depression determines the severity of their depression.

The characteristics associated with depression are affective, cognitive, and somatic.

For example, affective symptoms are the core symptoms of a depressed mood, and the term that one has a flat affect is an indication that one may be suffering from depression. These symptoms may include sadness, dissatisfaction, crying episodes, irritability, as well as social withdrawal. It should be noted that many events could cause the expression of such symptoms besides depression in itself.

Cognitive symptoms associated with depression may include pessimism, a sense of failure as well as guilt, suicidal ideation, and dislike of self.

Somatic symptoms may include insomnia, fatigue, weight change, and loss of interests, such as sex or other activities engaged in historically with a depressed patient. It should be noted that stress can cause such symptoms as well, in my opinion.

Recommended sites:

http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0020392
http://www.nimh.nih.gov/health/trials/practical/stard/index.shtml

Dan Abshear

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oliviapo said...

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